Marine Particles as Reservoirs of Novel Antimicrobial Peptides: An Emerging Frontier in Marine Drug Discovery

1. Introduction

Antibiotics have transformed modern medicine, making formerly lethal infections treatable and enabling procedures that depend on effective infection control, including surgery, transplantation, intensive care, cancer chemotherapy, and neonatal care [1,2,3]. Each year, hundreds of millions of people receive antibiotic treatment for infections. Ever since their discovery and widespread use, antibiotics have saved countless lives and significantly extended the average human lifespan [4,5]. However, the effectiveness and future achievements of antibiotics are threatened by antimicrobial resistance (AMR), a global ecological and evolutionary issue accelerated by antibiotic misuse and overuse in human medicine, animal production, agriculture, aquaculture, and the broader engineered and natural environments [6,7,8,9,10,11,12]. Worldwide estimates indicate that, in 2019, bacterial AMR was linked to approximately 5 million deaths [13], with over half a million of those occurring in China alone [14]. Systematic analyses predict that, without effective intervention, AMR could cause between 8 and 10 million deaths annually by 2050 [15,16]. These figures underscore AMR as one of the most pressing public-health and development challenges of the twenty-first century.

The slow pace of conventional antibiotic discovery exacerbates the AMR crisis [17,18,19]. Many antibiotics currently used in clinical settings target a limited set of conserved bacterial processes, such as cell wall biosynthesis, protein synthesis, DNA replication, RNA transcription, or folate metabolism [20,21]. The repeated targeting of these processes, combined with widespread antibiotic exposure, has selected for various resistance mechanisms, including reduced permeability, efflux, target modification, enzymatic inactivation, and biofilm-associated tolerance (Figure 1a) [11,20,21,22,23,24,25]. To make matters worse, most molecular mechanisms of AMR are associated with mobile genetic elements (MGEs), facilitating the global transmission of AMR through horizontal gene transfer (HGT) [26,27,28,29,30]. Multidrug-resistant pathogens, including those from the ESKAPE group [31,32,33,34,35,36], are now undermining the effectiveness of last-line therapies and highlighting the limitations of current discovery pipelines, which tend to rediscover variations of known drug scaffolds. This situation has sparked a renewed interest in developing antimicrobial agents with alternative structures, mechanisms, ecological origins, and evolutionary histories.

Antimicrobial peptides (AMPs), also referred to as host-defense peptides when produced by multicellular organisms [37,38,39,40,41,42], represent a promising new class of anti-infective agents [43,44,45,46,47,48,49,50,51]. Given the global threat of AMR, AMPs have come into the spotlight for their effectiveness against diverse microbial pathogens, including bacteria, fungi, protozoan parasites, and viruses [52,53,54,55,56,57]. For example, colistin, a cationic cyclic lipodecapeptide produced by Gram-positive bacteria of the genus Paenibacillus, is a last-line-of-defense antibiotic reserved for serious infections caused by multidrug-resistant Gram-negative bacterial pathogens [58]. Many AMPs act rapidly by directly interacting electrostatically with negatively charged microbial envelopes, leading to membrane permeabilization, pore formation, or destabilization. Some AMPs cross the microbial membrane and disrupt intracellular processes, impacting nucleic acid synthesis, protein translation, enzyme activity, and cell wall precursor cycling (Figure 1b) [57,59,60,61,62,63,64,65]. Beyond direct killing, many AMPs exhibit immunomodulatory, anti-inflammatory, antibiofilm, wound-healing, or synergistic activities, making them attractive not only as antibiotics but also as anti-infective adjuvants [39,64,65,66,67,68,69,70]. For instance, certain AMPs act as chemoattractants, recruiting host immune cells to sites of infection, while others help neutralize the cytotoxic effects of endotoxins, such as lipopolysaccharides (LPS) from Gram-negative bacteria, thereby preventing septic shock caused by excessive inflammation [71,72,73,74].

AMPs are typically short, cationic, and amphipathic peptides produced in all life forms, including bacteria, archaea, protists, fungi, plants, invertebrates, and vertebrates [42,75,76,77,78]. They constitute a critical component of the innate immune systems of fungi, plants, and animals, serving as the first line of defense against various pathogens [79,80,81,82,83,84,85,86]. AMPs exhibit a vast diversity in biological origins, sequences, lengths, structures, and bioactivities (Figure 2) [57,62,63,64,65,87,88]. Their defining advantages over traditional small-molecule antibiotics include remarkably broad-spectrum activity and rapid bactericidal kinetics [51,66,89,90,91,92,93]. Colistin (polymyxin E), for example, has been reserved as the last-line antimicrobial therapy for treating recalcitrant bacterial infections caused by multidrug-resistant pathogens [94]. Most critically, AMPs have a lower propensity than conventional antibiotics to promote bacterial resistance [92,95,96,97,98]. This resistance-avoidance property is largely attributable to the fundamental, non-specific, multi-target, and multifunctional nature of the AMP membrane-active mechanism, which creates a narrow time window and steep evolutionary barrier to microbial counter-adaptation [60,66,90,99,100]. There is also a low propensity for cross-resistance among different AMPs and between AMPs and antibiotics; instead, they typically demonstrate functional synergy, resulting in enhanced antimicrobial efficacy [67,97,101,102]. In addition, bacteria with multidrug resistance generally exhibit a high tendency toward collateral sensitivity to AMPs, a physiological phenomenon likely caused by antibiotic-induced changes in the lipopolysaccharide composition of the bacterial outer membrane [103]. Furthermore, limited functional compatibility poses a significant barrier to HGT of AMP resistance among phylogenetically distant bacteria [104]. As a result, their efficacy and low tendency to develop and spread resistance make AMPs “the most promising alternative to antibiotics” for the treatment of microbial diseases, particularly those caused by multidrug-resistant ESKAPE bacteria and WHO-priority fungi [105,106,107,108,109,110,111]. AMPs are highly regarded as the “pillars of next-generation antimicrobial agents” and “the game-changer in the epic battle against multidrug-resistant bacteria” [112,113].

AMPs are produced by virtually all cellular organisms, from prokaryotes to humans, as a means of signaling, competition, or defense [114,115]. They have evolved over billions of years in response to the diverse and ever-changing biological and physicochemical environments on planet Earth [116,117]. This extensive evolutionary history suggests that natural-based AMPs may possess nearly unlimited sequence diversity and remarkable functional versatility [118,119,120,121,122]. Microbial AMPs, in particular, play a substantial role in contributing to and expanding this vast chemical space [123,124,125,126,127,128,129,130,131]. Bacteriocins, lanthipeptides, lasso peptides, thiopeptides, microcins, and other ribosomally synthesized and post-translationally modified peptides (RiPPs) are produced by microorganisms as weapons, signals, and niche-structuring molecules [132]. These peptides can exhibit high potency, narrow or broad antimicrobial spectra, unusual post-translational modifications, and mechanisms distinct from those of many conventional antibiotics [133,134,135,136,137,138,139,140]. In addition to RiPPs, microbial AMPs can also be produced as non-ribosomally synthesized peptides (NRPs), a chemically rich and pharmacologically important class of peptidic natural products [141,142,143,144,145,146,147,148]. NRPs are biosynthesized by large modular non-ribosomal peptide synthetases (NRPSs), encoded by specific biosynthetic gene clusters (BGCs) [149,150,151,152]. The diversity and complexity of the BGCs and enzyme systems responsible for the cellular synthesis of RiPPs and NRPs yield an immense array of bioactive peptides [121,153,154,155,156,157,158,159], the vast majority of which remain undiscovered and unexplored [160,161,162]. Currently, both RiPPs and NRPs are experiencing a surge of research interest in genome mining and peptide engineering to generate non-natural peptides with enhanced or novel bioactivities, thereby further expanding the chemical space of AMPs [136,163,164,165,166,167,168,169].

Despite their vast diversity and inherent advantages over conventional antibiotics, only a handful of AMPs have successfully transitioned to clinical use to date [47,100,170,171,172,173,174], with challenges such as in vivo instability, systemic toxicity, and high manufacturing costs tempering early enthusiasm [37,75,175,176,177,178,179]. Nevertheless, the sustained acceleration of peptide engineering technologies, chemical modification strategies, and recombinant production platforms continues to drive a renaissance in AMP-based drug development [56,57,180,181,182,183,184,185,186]. In addition, recent innovations in genome mining and synthetic biology have demonstrated that previously undetected BGCs for RiPP and NRPs can now be rapidly identified, refactored, and expressed, yielding new AMP molecules with potentially novel bioactivities [96,187,188,189,190,191,192,193,194]. A central bottleneck, however, persists at the earliest stage of the AMP drug development pipeline: the identification of new lead sequences and novel scaffolds from underexplored biological and ecological origins [195,196,197]. This limitation reinforces the need to search for AMPs in unexplored and underexplored habitats where they have naturally evolved under chemically demanding, competitive, and fluctuating conditions [198].

The ocean, occupying approximately 71% of the Earth’s surface and 95% of the planet’s biosphere [199,200], harbors an extraordinary breadth of phylogenetic, metabolic, and ecological diversity that has been recognized since the mid-twentieth century as a prolific source of structurally unprecedented bioactive specialized metabolites [201,202,203,204,205]. As of June 1, 2026, the MarinLit database [206] documents 44,710 marine-derived metabolic compounds, showcasing a wide variety of structures and biological activities. These complex molecules reveal a vast chemical landscape with significant potential for pharmacological development and applications [195]. Landmark therapeutic translations include the anticancer drugs cytarabine (approved in 1969), eribulin mesylate (2010), brentuximab vedotin (2011), trabectedin (2015), plitidepsin (2018), and lurbinectedin (2020), as well as the analgesic drug ziconotide (2004), establishing the ocean as a vital forefront in natural product pharmacology [207,208,209,210,211,212,213,214,215]. Crucially, the past two decades have witnessed a decisive paradigm shift in marine natural products research: from a near-exclusive focus on sessile invertebrates (e.g., sponges, ascidians, and cnidarians) to the exploration of microorganisms and their communities, which often serve as the true biosynthetic producers of the valuable natural compounds identified from marine animals [216,217,218,219,220,221,222,223,224]. Microorganisms make up more than 95% of the total biomass in the ocean [225]. In particular, marine microorganisms represent a promising yet underexplored resource for bioactive peptides [226,227,228]. This refocusing has been further driven by advancements in cultivation-independent metagenomic technologies, which have revealed that the uncultured majority of marine microorganisms may represent a vast reservoir of novel BGCs for the biosynthesis of RiPPs and NRPs, as well as small open reading frames (smORFs) encoding AMPs that remain to be characterized and explored [192,229,230,231,232,233,234,235,236]. Another key factor fueling the search for new marine natural products is drug resistance. Beyond the issue of widespread antibiotic resistance in bacteria [9,34,237], cancer treatment drugs face the same challenge [238,239,240]. For instance, certain cancer cell lines have developed resistance to cytarabine and trabectedin, and cancer stem cells can enter a reversible dormant state to escape the therapeutic effects of eribulin mesylate and brentuximab vedotin [241]. The arms race between cellular (including microbial) evolutionary processes and human efforts to combat disease will probably never end, keeping the marine environment a central arena for drug discovery and development.

Within the marine ecosystem, particulate organic matter — collectively termed marine particles — constitutes a ubiquitous, unique, and microbiologically active microhabitat in the vast water body of the ocean [242,243,244]. These particles, which range in size from sub-micron colloidal aggregates to centimeter-scale macroscopic flocs, are continuously generated in the euphotic zone through the coagulation of phytoplankton exudates, cellular debris, zooplankton fecal pellets, and other organic matrices [245,246,247,248,249,250]. Marine particles play critical roles in the ocean’s biogeochemical cycling and climate regulation [251,252,253,254,255]. As they descend through the water column, they serve as concentrated oases of labile carbon and nutrients amidst the vast oligotrophic pelagic background, supporting microbial population densities that can exceed those in the surrounding seawater by three to five orders of magnitude [256,257,258,259]. Critically, this extraordinary enrichment transforms marine particles into intense arenas of microbial competition and antagonism, where densely packed, phylogenetically diverse assemblages of bacteria, archaea, protists, fungi, metazoa, and viruses engage in fierce, sustained ecological interactions for space and resources [243,260,261,262,263,264,265,266,267,268,269,270]. Moreover, the composition of particle-associated microbial communities differs from that of free-living microbial communities [243,271], thus enhancing the potential for functional innovation in marine microbiomes. It is precisely this elevated level of biotic conflict and functional novelty that positions marine particles as putative “hotspots” for the evolution, expression, and diversification of marine AMPs.

Marine-sourced peptides are at the forefront of novel natural product discovery and therapeutic drug development [272,273]. In this perspective article, we propose that marine particles represent a promising yet underexplored frontier for the discovery of marine AMPs. We synthesize current knowledge spanning marine microbial ecology and potential applications to evaluate the proposition that marine particles constitute a vast, untapped reservoir of novel marine AMPs. By connecting the global need for new anti-infective strategies with the ecological function of AMPs and the unique microscale ecology of marine particles, we highlight a conceptual shift: marine particles should not be viewed only as micro-reactors for important ecological and biogeochemical activities, but also as chemically active, interaction-rich niches where AMPs may evolve, accumulate, and function. Exploring these marine particle-associated peptide repertoires could expand the known diversity of AMPs and provide new leads for combating antibiotic-resistant infections and beyond.

2. Marine Particles: Ecology-Driven Hotspots for AMP Discovery

Life likely originated in the ocean [274,275], which currently hosts more living species than land does [276]. Populated by an estimated 10 billion microbial species [277], the ocean presents a fundamentally distinct biological and chemical landscape, where varying hydrostatic pressures, temperatures, salinities, and biological interactions create a variety of habitats that have driven the evolution of unique metabolic pathways and bioactive compounds not found in terrestrial ecosystems [278,279,280,281,282]. Anthropogenic perturbations, such as eutrophication, pollution, excessive CO2 emissions, and the resulting ocean warming, acidification, hypoxia, and harmful algal blooms, impose additional stresses on marine organisms, forcing them to adapt to changing environments and unseen biological interactions [283,284,285,286,287,288,289,290,291,292,293]. Biochemical and metabolic innovation, the key to ecological adaptation and physiological tolerance in such challenging and competitive environments, may yield novel molecules with unprecedented chemical scaffolds or enhanced specificity and potency—qualities that are increasingly critical as resistance to conventional therapeutics becomes more prevalent [294,295,296,297,298,299,300]. Moreover, marine biodiversity remains vastly unexplored, with less than 1% of marine microorganisms successfully cultured, less than 0.01% characterized, and far fewer screened for their bioprospecting potential [301]. To put this into perspective, it is estimated that fewer than one in a trillion microbes in soil have ever been screened globally for antibiotic activity [302], even though the terrestrial environment has been explored significantly more extensively than the marine realm. The ocean’s vast biological and environmental diversity highlights an enormous, untapped resource for pharmacologically relevant discoveries [234].

However, exploring this immense ocean comes with considerable challenges. To date, for example, only a tiny fraction (<0.01%) of the deep-sea floor has been thoroughly investigated [303]. In fact, it is simply not feasible to sample every milliliter of seawater or every gram of marine sediment. Moreover, not all seawater or sediment is the same. Some marine habitats are more abundant in natural product diversity than others due to specific environmental conditions and prevalent biological interactions [219]. Strategic habitat selection is essential in the quest to discover novel AMPs because habitats not only serve as sampling locations but also act as evolutionary filters [299,302,304,305,306,307]. Each habitat has its unique evolutionary history in natural product chemistry and imposes distinct physical, chemical, and biological selection pressures that influence the repertoire of AMPs and the likelihood of discovering novel ones. Recent global microbiome studies have confirmed that AMPs are indeed habitat-specific [235,308,309]. Effective abiotic and biotic factors—including temperature, salinity, pH, oxygen levels, pressure, microbial density, symbiosis, competition, amensalism, and antagonism (such as predation, parasitism, and pathogenesis)—can affect which AMPs are created, retained, diversified, transferred, and expressed within a given habitat [122,310]. Recent reviews indicate that marine environments produce AMPs with distinct structures, chemical modifications, amino acid preferences, salt tolerance, specialized membrane-targeting behaviors, and bioactive functions compared to AMPs from other habitats, suggesting an ecological adaptation of marine peptide chemistry [311,312]. A notable example is digitiferin, a novel AMP identified from Acropora digitifera. Its bactericidal activity against the coral pathogen Vibrio coralliilyticus is evident only under the low-salt conditions found in coral mucus, rather than at bulk seawater salinity [313]. Such a finding is strategically significant. Without an understanding of the habitat’s microenvironment and ecological complexity, a potential AMP could easily be overlooked during screening. Therefore, ecology-driven habitat selection is crucial for the discovery of natural products, and targeted investigations guided by habitat prioritization can greatly increase the likelihood of finding novel AMPs rather than repeatedly rediscovering known compounds and their close analogs.

Nowadays, bioprospecting for marine natural products primarily focuses on two types of marine habitats. The first type includes environments with significantly high densities of microorganisms and complex interactions, such as the holobionts of marine sponges, corals, and ascidians, the mucus layers found on marine invertebrates and vertebrates, and the biofilm communities [311,314,315,316,317,318,319,320,321,322,323,324,325]. Such habitats are the biological “front lines” where AMPs are under continuous, direct selection pressure for defense and competition, driving their structural and functional diversification. The second type consists of challenging and extreme marine environments, such as mangrove sediments, polar oceans, and deep-sea and hadal trench sediments [282,308,326,327,328,329,330,331]. Extreme environmental conditions, such as rapid salinity shifts, low temperatures, and high hydrostatic pressures, in such habitats impose unusual stability and functional constraints on AMPs, driving their structural innovation. Some habitats, such as deep-sea hydrothermal vents and cold seeps, fall into both categories [234,308,332,333,334,335,336,337,338,339]. In such habitats, where high microbial abundance and environmental extremity coexist, both biological and environmental selection pressures are at play. In addition to these traditionally targeted habitats for natural product discovery, the vast oceans likely harbor other promising habitats that warrant exploration. Modern AMP discovery is increasingly focused on marine microorganisms and is becoming progressively more genomics- and metagenomics-driven [233,320,323,340,341,342,343,344,345,346,347]. Recently, a marine particle-targeted investigation identified hundreds of microbial BGCs encoding diverse RiPPs, NRPs, and non-ribosomal peptide-polyketide hybrids [348]. This study highlights marine particles as hotspot (micro)habitats for natural product bioprospecting, supporting the long-held hypothesis that marine particle-associated bacteria could be a rich source of unexplored antimicrobial agents [260,304,349,350].

Most microorganisms lead social lifestyles characterized by diverse interactions [351,352,353]. In marine particle-associated microbiomes, various forms of cooperation, as well as competitive and antagonistic interactions, are common among microorganisms [243,261,348,354,355]. Intuitively, microorganisms employ competitive and antagonistic mechanisms to exclude competitors and monopolize shared resources such as nutrients, electron donors/acceptors, and space. Competition is a key factor in both the evolution of species within a population and the coevolution of multiple species in a community by driving microbial innovation to improve fitness and strengthen defense mechanisms [353,356]. However, counterintuitively, competition can also promote the stability and resilience of microbial communities [357]. In complex or spatially structured environments, such as biofilms and marine particles, competition can lead microorganisms to occupy distinct niches, either temporally or spatially [358]. This process enhances biodiversity and supports community succession through niche construction and partitioning, providing a strategy for adaptation to complex or changing environments [243,264,348,357,359]. Additionally, interspecies competition can stimulate both intraspecies and interspecies cooperation among collaborating partners, helping stabilize the interaction network of keystone species and, consequently, the core functions of a microbial community [356]. Therefore, the balance between competition and cooperation is crucial in shaping the community structure, dynamics, and ecological functions of the marine particle-associated microbiomes [360]. An in-depth understanding of microbial interactions and the ecological and evolutionary constraints that determine their distribution and dynamics in the ocean may aid in bioprospecting for marine AMPs.

Marine particles create unique ecological conditions that differ from the surrounding seawater. These particles concentrate organic carbon, nitrogen, phosphorus, trace metals, extracellular enzymes, metabolites, extracellular genetic materials, and microbial cells. They also create microscale gradients in oxygen, pH, redox state, and nutrients [243,258]. Such gradients promote spatial structuring and metabolic specialization among microorganisms. In densely colonized marine particle microhabitats, microorganisms compete for attachment sites, nutrients, and other resources, while antimicrobial compounds can provide selective advantages. As a result, marine particles may function as evolutionary microincubators for structurally diverse AMPs in the ocean. Numerous studies indicate that marine particles are characterized by steep physicochemical gradients, variable availability of nutrients and electron donors/acceptors, extremely high microbial densities and activities, rapid colonization–succession dynamics, biofilm-like structural organization, frequent chemical signaling, spatial confinement of competing taxa, and high incidences of antibiotic resistance genes and HGT [243,249,257,258,264,279,361,362,363,364,365,366,367,368,369]. These conditions intensify direct microbial competition and quorum-regulated chemical warfare [243,370,371,372,373,374,375,376], in which antimicrobial compounds may function as arsenals for competitive exclusion and chemical defense [324,354,377,378]. Multiple studies highlight that particle-associated microbial assemblages undergo rapid succession from primary degraders to secondary consumers [379,380], creating repeated interaction windows in which antagonistic traits—including AMP production—are likely to be selectively favored. As a result, marine particles transform the ocean from a dilute system, dominated by random microbial encounters, into a structured arena of deterministic microbial competition and antagonism. Metagenomic reconstruction of particle-associated microbial communities provides direct evidence that these habitats are enriched in biosynthetic potential. The particle-associated fractions contain diverse BGCs encoding RiPPs and NRPs. More importantly, expression-level analyses demonstrate that particle-associated lifestyles are associated with elevated transcription of secondary metabolite genes compared with free-living fractions [348]. These findings indicate that marine particles are not only reservoirs of latent biosynthetic potential but also active sites of secondary metabolite expression, reinforcing their relevance as functional AMP discovery hotspots.

Microbial community analyses reveal that marine particles are inherently multi-domain ecosystems [269,381]. Within these ecosystems, bacteria are the dominant colonizers of marine particles [243,266,382,383]. In particular, bacteria phylogenetically affiliated with competitive, copiotrophic groups that are adapted to rapid substrate exploitation and surface colonization likely dominate the AMP-relevant biosynthetic pathways [250,380,384]. In addition, several archaeal taxa have been recognized as an inherent component of the marine particle-associated microbiomes [385,386,387]. As the third domain of life on Earth, archaea possess unique cell membrane structures, distinct cell wall compositions, and extraordinary metabolic potentials alongside specialized stress-adaptation mechanisms not found in bacteria and eukaryotes [388]. These wide ranges of uniqueness suggest that archaea may also innovate to produce novel AMPs with distinct structural, mechanistic, and functional properties [389], equipping them with specialized molecular weaponry for ecological competition, defense, and survival in their environments. Indeed, recent proteome and (meta)genome mining efforts have revealed thousands of archaeal peptide candidates [337,347,348,390,391,392,393,394,395]. Some archaeal peptides have been experimentally validated to have antimicrobial activity against bacterial pathogens [347,395,396,397]. A recent investigation found that archaea have a higher density of smORFs than bacteria at the phylum level [398]. These previously overlooked potentials suggest that archaeal participation in marine particle-associated communities may expand the diversity of marine AMPs. Moreover, marine fungi have recently been found to colonize marine particles, a previously overlooked component of particulate microbiomes [381,399,400]. The biomass of fungi in the global ocean exceeds that of archaea by nearly one order of magnitude [401], and they actively participate in oceanic biogeochemical cycles by mediating enzymatic activities that degrade polysaccharides and proteins [270,402]. Their ability to produce cyclic peptides, depsipeptides, and other peptide-derived metabolites positions marine fungi as complementary sources of antimicrobial scaffolds [125,403,404,405,406,407,408], particularly in competitive detrital and biofilm-like particle environments. The competition among archaea, bacteria, and fungi intensified within confined particulate microenvironments likely represents an underexplored dimension of AMP evolution. Collectively, these prokaryotic and eukaryotic microorganisms form a convergent ecological unit in which inter-domain interactions may amplify the selective pressures that drive the development of new AMPs with unique structures and functions.

A defining but often underappreciated property of marine particles is their environmental heterogeneity in the ocean [248,409]. These particulate structures are ubiquitous throughout the entire water column, ranging from the sunlit surface waters to the deepest hadal environments. As a result, marine particle-associated microbial communities are exposed to a wide range of physicochemical conditions, including variations in temperature, pressure, oxygen levels, redox states, and substrate composition [410], thereby expanding the chemical landscape of antimicrobial evolution. Once formed, marine particles are rapidly colonized by various microorganisms, which often engage in dynamic, complex interactions and community succession as they sink to deeper waters [243,264,266,411,412,413]. The productive epipelagic zone is rich in phytoplankton-derived fresh aggregates, while the mesopelagic twilight zone is a hotspot environment for POM remineralization [414,415,416,417,418,419,420]. Although aged particulate materials populate the bathypelagic and abyssopelagic zones, particle association remains important, as over 95% of DOC is refractory to microbial utilization here [421,422]; thus, marine particles provide the primary source of organic carbon and energy for the survival and activity of both particle-associated and free-living microbes [271,418,419,423,424,425,426,427]. Interestingly, the hadopelagic zone hosts particle-associated microbial communities that likely exhibit enhanced metabolic activities, including both chemolithoautotrophy and heterotrophy, despite the extreme pressure conditions [428]. Such stratification indicates that marine particles do not represent a single ecological niche; rather, they comprise a globally distributed system of microhabitats that support distinct microbial communities and functions, expanding the chemical search space for marine AMP discovery.

The discovery of novel AMPs from marine microorganisms remains constrained by inadequate ecological targeting of biosynthetically rich and active habitats. Marine particles, such as phytodetritus, fecal pellets, transparent exopolymer particles, and detrital aggregates, function as discrete, nutrient-confined microhabitats embedded within the oligotrophic ocean matrix. They are active ecological “microreactors” where microbial interactions are intensified and metabolically costly traits, including antimicrobial production, become selectively advantageous. Throughout the immense oceanic gradients—from the euphotic surface waters to the mesopelagic twilight zone and further into the deep dark ocean and hadal zone—marine particles promote the expression of secondary metabolite BGCs, representing globally distributed yet underexploited resources that should be prioritized for uncovering structurally and functionally novel AMPs across marine bacteria, archaea, and fungi. Marine particles are not simply reservoirs of microbial life—they are engineered by nature as competitive arenas where antimicrobial chemistry is continuously selected, tested, and diversified. Prioritizing these systems, therefore, represents not only a methodological improvement but also a conceptual advance in our understanding of and search for AMPs in the global ocean.

3. Metagenomics: The Horsepower Driving Marine AMP Discovery

The ocean harbors the largest biome of microorganisms, with a tremendous diversity of taxa and functions. The extensive microbiomes in the world’s oceans have evolved over billions of years under a variety of challenging abiotic and biotic conditions, resulting in remarkable genetic and biosynthetic potential that is largely untapped [225,429,430,431,432]. According to the International Census of Marine Microbes (ICoMM), the ocean contains approximately 3.6×1030 microbial cells [433]. In just one liter of seawater, there can be over 100 million microbes, representing up to 20 thousand different bacterial species [429,433]. Marine particles, in particular, often have much higher microbial densities [256,257,258,259], making them an immense resource for AMPs. However, most marine microorganisms remain difficult, or even impossible, to cultivate [434,435], limiting the targeting of their biosynthetic capabilities in traditional natural product discovery.

Historically, marine natural product discovery has led to the identification of numerous bioactive compounds [201,203,205,436,437,438], yet the vast majority of marine microbial diversity remains poorly characterized and uncultivated. The traditional process of discovering natural products faces significant challenges, including high costs, time demands, and the need for early dereplication to eliminate metabolite candidates that have already been identified [439,440]. Consequently, only a small fraction of marine biosynthetic potential has been captured to date. To tackle these issues, it is strategically important to focus on underexplored biological resources or environments, such as marine particles, to increase the yield of previously uncharacterized chemical structures [430,441,442]. Additionally, metagenomics is revolutionizing this field by providing a central means of accessing hidden, unculturable diversity. Metagenomics, particularly genome-resolved metagenomics, overcomes the limitations of microbial cultivation, enabling the direct mining of genes and BGCs from complex environmental microbial communities for AMP discovery [192,233,345,431,443,444]. Metagenomics is the enabling engine that converts environmental microbial dark matter into a searchable chemical possibility (Figure 3). When coupled to genome-resolved reconstruction, metagenomics can link antimicrobial candidates to taxa, ecological niches, and evolutionary contexts [445,446,447]. When coupled to machine learning and deep learning, it can prioritize peptide candidates from billions of sequences [448,449,450]. When coupled to synthetic biology and robust activity validation, it can generate experimentally testable molecules at an unprecedented scale [451,452,453]

The rare biosphere is increasingly recognized as a reservoir of functional novelty [454,455,456,457,458,459]. Low-abundance microorganisms may experience unique evolutionary pressures, thrive in specific environmental conditions, and produce specialized metabolites absent from dominant taxa [323,460,461]. Rare species may be prevalent and particularly important in the marine particle-associated microbiomes. Marine particles are transient, heterogeneous, and rich in unique microenvironments, allowing rare taxa to flourish under certain emerging conditions and persist if they can provide core functions or occupy stable micro-niches [462]. In densely populated marine particle-associated communities, rare taxa may use AMPs to compete, survive, and respond to environmental and interspecific challenges. Although rare microorganisms are often low in abundance, they can be rich in biosynthetic variety [463,464]. As a result, marine particle-focused metagenomics, particularly through deep sequencing [465], may uncover a surprising diversity of bioactive peptides.

An important frontier in marine natural product discovery is the identification of AMPs encoded by smORFs [235,320,346,466]. Conventional genome annotation pipelines often overlook these short ORFs, treating them as noncoding noise or unlikely candidates for protein-coding regions [467,468,469]. However, small peptides can possess potent biological functions, including antimicrobial activity, signaling, stress response, and membrane interaction [470]. As a result, smORF-encoded peptides (SEPs) are now seen as hidden treasures in the search for AMPs [470]. This is especially relevant for metagenomic datasets, where short peptide-coding regions can be abundant but difficult to distinguish from random ORFs. Consequently, conventional bioinformatics methods tend to yield a high rate of false-positive predictions [471]. Recent advances driven by artificial intelligence (AI), including machine learning and deep learning, have effectively addressed this issue by enabling the screening of large sequence spaces for AMP-like characteristics with much improved accuracy [236,395,472,473,474,475]. Deep learning, in particular, has shifted AMP discovery from small-scale screening toward large-scale prediction and design. Traditional AMP identification depended on known sequence motifs or physicochemical filters. Modern deep learning models can learn higher-order sequence patterns and predict activity from large peptide datasets [476,477,478]. The discovery of bioactive SEPs from environmental microbiomes has been further accelerated by integrating genome-resolved metagenomics with other state-of-the-art meta-omics analytical platforms, such as metatranscriptomics, ribosome profiling, and metaproteomics [236,320,470,472]. For marine particle samples, these techniques can reveal which SEP genes are actively expressed under specific ecological conditions. For instance, expression levels may increase during particle colonization, nutrient depletion, competitor invasion, or environmental stress. By integrating DNA-based metagenomics with RNA- and ribosome-level data, AMP discovery can become more biologically relevant.

Other important classes of peptides include RiPPs and NRPs, the synthesis of which is linked to specific BGCs [136,137,140,149,152]. Genome- and metagenome-based BGC screening is transforming the discovery of microbial RiPPs and NRPs. Traditionally, the discovery of natural products has relied on a series of steps: isolation, cultivation, extraction, bioactivity screening, and chemical characterization. While this strategy remains valuable, it is insufficient to capture the full biosynthetic diversity present in marine microbiomes. Most marine microorganisms are difficult to cultivate [434,435], and many BGCs are silent under laboratory conditions [479,480,481,482,483,484], making them difficult to discover. Additionally, repeated screening efforts often result in the rediscovery of known compounds. Genome and metagenome mining overcomes these limitations by uncovering the biosynthetic potential prior to cultivation and metabolite isolation [485,486]. This innovative approach operates at high speed and throughput. When combined with AI-driven models for big data analysis and prediction [161,432,441,487,488,489,490,491], it significantly improves the detection rate of novel natural product-encoding BGCs in microbial genomes and metagenome-assembled genomes (MAGs).

Genome sequencing and analysis have revealed that microorganisms possess many more BGCs than traditional laboratory screening methods could detect [192,480]. Large-scale metagenomic studies of oceanic environments have shown that marine microbial communities encode vast numbers of previously uncharacterized genes, many of which lack close homologs in existing reference databases [492]. Recent metagenomic analyses of marine microbial communities, including those at a global ocean scale, have uncovered extensive biosynthetic potential, including abundant BGCs for RiPPs and NRPs [233,234,337,338,341,493,494]. These studies indicate that marine microorganisms produce not only simple ribosomal AMPs, such as SEPs, but also more complex peptide molecules, such as RiPPs and NRPs. The RiPP class encompasses various types of peptides, including ribosomally synthesized lanthipeptides, lasso peptides, thiopeptides, microcins, and other modified peptide families. In contrast, the highly diverse NRPs are synthesized nonribosomally by multimodular NRPSs. Many SEPs, RiPPs, and NRPs exhibit antimicrobial activity, making them promising targets for marine metagenomic discovery.

Marine particles represent spatially concentrated reservoirs of antimicrobial genetic potential, and metagenomics provides the core methodological engine for recovering all three major peptide-discovery targets: genes encoding SEPs and distinctive classes of BGCs for RiPPs and NRPs, respectively. For marine AMP discovery, BGC mining complements smORF and peptide prediction. Some AMPs are encoded by simple, small genes, while others require modifying enzymes, transporters, immune proteins, and regulatory elements. A comprehensive AMP discovery pipeline should therefore include both direct peptide prediction and BGC-aware mining. Although these three classes are often discussed together under the broad label of peptide natural products or AMPs, and they all can be mined from metagenomic data, they require different analytical strategies. RiPPs are ribosomally encoded but post-translationally modified, and their discovery depends on recognizing both precursor peptides and tailoring enzymes. NRPS products (i.e., NRPs) are assembled by large modular enzymes rather than being directly translated from a peptide gene, and thus NRPS discovery depends on predicting both the architectures of modular enzymatic domains and their substrates. A typical NRPS module contains adenylation, thiolation, and condensation domains. Adenylation domains select substrates; thiolation domains carry activated monomers; and condensation domains form peptide bonds. In addition, thioesterase domains (i.e., the termination domains located exclusively on the final module of a complete NRPS assembly line) release or cyclize products, and auxiliary modifying domains catalyze epimerization, methylation, hydroxylation, halogenation, or ring formation. So the lengths of BGCs encoding functional NRPSs can typically reach tens and even hundreds of kb [151,152,495]. SEPs are short ribosomal peptides encoded by smORFs that may lack an obvious biosynthetic context and are easily missed by conventional annotation, and their discovery depends on sensitive short-gene detection, coding-potential assessment, and downstream AMP prediction.

Different analytical strategies require specific technical details. Short-read sequencing is commonly used in metagenomic studies due to its high accuracy and depth. This method is suitable for community profiling, gene catalog construction, and the detection of abundant genes [496]. However, while metagenomes derived from short-read sequencing may not significantly influence the discovery of smORFs, short reads can fragment BGCs and complicate strain-resolved assembly [497]. These problems pose challenges for mining BGCs for RiPPs and NRPs. RiPP BGCs can be disrupted if precursor genes and genes for tailoring enzymes are located on separate contigs, making BGC mining difficult or even impossible. BGCs that encode NRPSs are often large, repetitive, and modular. Thus, gene cluster fragmentation may disrupt module boundaries and repeated domains, leading to truncated BGCs that do not produce mature, functional peptides. Long-read sequencing can improve assembly contiguity and aid in the recovery of complete BGCs [345,498,499]. Hybrid approaches that combine the accuracy of short-read sequencing with the scaffolding capabilities of long-read sequencing are particularly valuable for the metagenomic analysis of RiPPs and NRPSs [500,501,502]. The discovery of smORFs also benefits from accurate metagenome assemblies and error correction, though it is less dependent on the long-range continuity of BGCs.

Studies of microbial communities show that marine particles harbor dense bacterial populations whose activities transform and degrade particulate organic materials [261,503]. The high density of microbial cells and high microbial metabolic activities on marine particles increase the probability of competition and antagonism [250,379]. Microorganisms attached to the same marine particle may compete for carbon sources, nutrients, electron donors/acceptors, metabolic by-products, and microniches on and inside marine particles [243]. Under such spatially confined conditions, antimicrobial molecules may serve ecological functions by inhibiting competitors, shaping community structure, protecting producer lineages, or mediating colonization and community succession. Thus, marine particles create localized, resource-rich microenvironments within surrounding oligotrophic seawater. Additionally, there is significant microscale variability both within and between these marine particles [243,504]. Therefore, ecology-focused AMP discovery should be conducted with single-particle precision [380,505,506]. Employing single-particle sequencing and metagenomic studies will enhance our understanding of the intricate ecological interactions, their variations, and dynamics within the microbiomes colonizing individual marine particles, as well as their ecological roles in the evolution and expression of AMPs in these hotspot microenvironments.

4. Potential Applications of Marine AMPs in Human Medicine

The global crisis of antimicrobial resistance has created an urgent need for new anti-infective agents with a low likelihood of inducing pathogen resistance [9,10,11,12]. Marine AMPs represent a highly promising class of bioactive molecules with broad potential applications. Many marine AMPs exhibit unique structural features that are superior to those of conventional small-molecule antibiotics, including rare heterocyclic scaffolds, modified non-proteinogenic residues, and salt-tolerant, lipophilic backbones, evolved to help host microbes thrive in specialized, competitive marine environments [201,507]. Their generally rapid, multi-target antimicrobial actions, along with their effectiveness against diverse bacteria, fungi, parasites, and viruses, make marine AMPs attractive candidates for addressing the growing challenge of antimicrobial resistance and for developing next-generation anti-infective products [312,508,509]. Potential applications for marine AMP candidates include novel topical anti-infectives, wound-healing formulations, antibiofilm coatings for medical devices, and immunomodulatory therapeutics [510,511,512,513].

Unlike many antibiotics that target a single conserved enzyme or biosynthetic pathway, AMPs often employ multiple mechanisms to exert their effects. These mechanisms include destabilizing membranes, causing rapid depolarization, forming pores, remodeling cell envelopes, binding to intracellular targets, regulating the immune response, or employing multimodal approaches [47,49,56,87,201,437,514,515,516]. This ability to target multiple pathways or cellular structures can reduce, though not eliminate, the likelihood of resistance development [66,103,228,517,518,519,520,521]. Many marine AMPs act through electrostatic attraction to microbial membranes, followed by processes such as insertion, thinning, curvature induction, membrane permeabilization, or pore formation [201,507]. The membrane-targeting nature of AMPs offers several therapeutic advantages. Their killing action can be rapid, and modifying the target may be more challenging than simply mutating a single cellular component or enzyme. However, membrane activity also raises safety concerns. Excessive hydrophobicity or poor selectivity can lead to issues such as hemolysis, toxicity to mammalian membranes, or local tissue irritation [109,521,522,523,524,525]. Therefore, modern developments in AMPs focus on maximizing pathogen selectivity rather than solely disrupting membranes. Some marine AMPs have been found to interfere with intracellular processes or components [308]. These mechanisms are therapeutically significant, as they may enhance selectivity, reduce host-cell damage, and confer drug-like effects similar to those of traditional antibiotics while retaining the advantageous ability of AMPs to penetrate cells. Moreover, due to their long-term adaptation to the marine environment, certain marine AMPs can maintain their antimicrobial efficacy under physiological ionic conditions, showcasing promising therapeutic potential [526].

Many bacterial and fungal pathogens form biofilms that lead to persistent infections, increased antibiotic resistance, and the ability to evade host immune responses [22,527,528,529,530,531]. Biofilms play a significant role in various disease conditions, including chronic wounds, catheter infections, prosthetic joint infections, dental and airway infections, and recurrent urinary tract infections [532,533,534]. Some marine AMPs have shown strong antibiofilm activity. They prevent microbial adhesion, reduce extracellular polymeric substance production, inhibit biofilm maturation, disrupt microbial membranes within biofilms, block quorum-sensing signals, downregulate virulence toxin gene expression, promote degradation of the biofilm matrix, or enhance immune clearance [508,511,512,535,536,537,538,539,540,541,542]. These properties make marine AMPs highly attractive for developing coatings for catheters, implants, wound dressings, contact lenses, and dental materials, as well as marine-inspired anti-infective therapeutics and biomaterials.

Marine AMPs represent a promising but still underdeveloped class of therapeutic agents and drug leads. Beyond direct antimicrobial activities such as direct killing, antivirulence, and antibiofilm effects, some marine AMPs also exhibit antifungal, antiparasitic, antiviral, anti-cancer, anti-proliferative, anti-inflammatory, antioxidant, anti-diabetic, antihypertensive, antithrombotic, anticoagulant, anti-obesity, anti-allergic, anti-aging, antifatigue, and wound-healing activities [54,55,70,157,201,204,210,227,321,405,436,437,543,544,545,546,547,548,549,550,551,552,553,554,555,556,557]. Marine AMPs are structurally diverse molecules, including α-helical peptides, β-sheet disulfide-rich peptides, cyclic peptides, lipopeptides, and non-ribosomal peptide derivatives, offering great potential for a broad range of therapeutic applications [510,511]. For systemic therapy, substantial progress is needed in stability, selectivity, delivery, pharmacokinetics, and safety of marine AMPs [201,437].

Beyond their applications in human medicine, marine AMPs also hold promise in various other fields. In agriculture, AMPs offer potential as environmentally compatible alternatives or complements to conventional antibiotics and chemical pesticides, effectively suppressing bacterial and fungal phytopathogens, controlling pest insects, enhancing crop disease resistance, and reducing the selection pressure for antibiotic resistance within integrated plant protection systems [437,438]. In aquaculture, where infectious outbreaks and antibiotic dependence remain persistent challenges, marine AMPs may be developed as disease control agents, functional feed additives, immunostimulatory compounds, or antimicrobial surface coatings to improve the health and resilience of farmed fish and shellfish [558,559,560]. Other applications of marine AMPs include veterinary medicine [561], food preservation and safety [321,437,562,563], nutraceuticals [321], cosmeceuticals [321,437,562,563], and the prevention of biofouling and biocorrosion [511,536,537,564,565,566,567,568]. Given this translational potential, the ocean—particularly the marine particles within it—represents an underexplored source of AMP-producing microorganisms and peptide diversity, underscoring the need for in-depth investigation.

5. Perspectives

The next frontier in marine AMP discovery will require a transition from sequence-centered prospecting to ecology-informed functional bioprospecting. Rather than viewing marine particles merely as passive carriers of microbial diversity, they should be regarded as dynamic evolutionary microhabitats in which microbial competition, antagonism, chemical communication, and environmental heterogeneity collectively shape the emergence and expression of antimicrobial traits. Future investigations should therefore integrate single-particle ecology, genome-resolved metagenomics, metatranscriptomics, metaproteomics, metabolomics, and spatial imaging to identify not only which AMP genes are present but also when, where, why, and how they are expressed during particle colonization, microbial community succession, and interspecies interactions. Such an ecological framework will enable researchers to distinguish constitutively encoded peptides from environmentally induced antimicrobial molecules and to prioritize AMP candidates with demonstrated ecological functions. Equally important, coupling these multi-omics datasets with artificial intelligence, structural prediction, synthetic biology, and high-throughput functional validation will establish an end-to-end discovery pipeline that links environmental selection pressures to peptide structure, biological activity, and translational potential, thereby substantially improving the efficiency of identifying truly novel antimicrobial scaffolds from the vast uncultivated marine microbiome [192,229,231,235,395].

More broadly, this review advocates a conceptual shift in marine natural product discovery. The greatest opportunities may no longer lie simply in sampling unexplored marine organisms or environments, but in identifying ecological systems where natural selection continuously drives chemical innovation. Marine particles represent precisely such systems, functioning as globally distributed microscale arenas in which antimicrobial chemistry is repeatedly generated, tested, and refined through intense microbial interactions. As antimicrobial resistance continues to outpace conventional antibiotic discovery, integrating marine microbial ecology with natural products chemistry, computational biology, and peptide engineering offers a promising strategy for expanding the chemical space of next-generation anti-infective agents. Although substantial challenges remain—including experimental validation, scalable production, pharmacokinetic optimization, and clinical translation—the convergence of ecology-guided habitat prioritization, cultivation-independent (meta)genomics, and AI-enabled prediction and molecular design is poised to transform marine particle-associated microbiomes into one of the most productive frontiers for future AMP discovery. Ultimately, understanding why AMPs evolve in nature may become as important as identifying the peptides themselves, providing a new ecological paradigm for marine drug discovery.